Across 1,000 genomes, rarities abound

Every person’s genetic instruction book is a trove of never-before-seen genetic variants, according to an ongoing effort to map human genetic diversity.

In recent years, scientists have discovered that humans carry far more rare genetic variants than anyone ever thought. Now, a major effort to map the diversity of humans’ genetic makeup — called the 1000 Genomes Project — has turned up even more variety than researchers had expected. The project has now lived up to its name, completing a comprehensive sampling of 1,092 people from 14 different populations around the world, an international consortium of researchers reports in the Nov. 1 Nature.

Among the anonymous people sampled, researchers found 38 million single DNA unit changes, known as SNPs. Of those, about two-thirds are newly discovered and many are rare, found in less than 0.5 percent of people. These variants, along with small and large insertions and deletions and rearrangements of DNA, may affect health and disease risk and can help scientists trace humans’ migrations around the globe.

“The magnitude of rare variation observed in human populations has really been driven home to everyone,” says Nancy Cox, a quantitative human geneticist at the University of Chicago. Large numbers of rare variants in the 1,092 study participants indicate that human population growth has been “superexponential,” Cox says.

Rare variants tend to be new variants, springing afresh in every generation as DNA-copying machinery makes occasional typos. The more people added to a population, the more rare variants are added, too.

Genetic bottlenecks created when populations are squeezed by disaster, disease or migration haven’t wrung the multitude of variants out of the human genome yet, as scientists thought might happen. The researchers see evidence that evolution is at work, selecting against changes to many parts of the genome, but evolutionary forces have not had time to act against some of the freshest variants.

Meanwhile, how rare variants contribute to common diseases such as diabetes, heart disease and other conditions is still a matter of debate. “It’s almost unimaginable that it won’t make some contribution,” says Cox, who heads the University of Chicago’s genetic medicine section.

Scientists in the 1000 Genomes consortium attempted to get a handle on how much rare variants might contribute to disease risk, says Gil McVean, a statistical geneticist at the University of Oxford in England, and one of the project’s leaders. Among rare variants that would change the chemical makeup of a protein, one-quarter to one-half are predicted to damage the proteins functionally, the researchers found. On average, each person carries an estimated 76 to 190 of these rare variants, plus up to 20 more that either completely inactivate or cause a protein not to be made or have already been associated with disease. Each person probably carries one or two such variants previously implicated in cancer.

In addition to variants that alter proteins, the researchers found a plethora of others — many of them also rare — in parts of the genome that control gene activity. Such variants may have an important role in disease by altering switches in genes’ control panels so that genes become too active, insufficiently active or active at inappropriate times. Each person carries about 700 to 900 variants that remove particular switches from genes’ control panels, including an estimated 18 to 69 that are rare and show evidence that evolution is weeding them out.

Variants that add new gene-control switches are less common, with people carrying about 200 such additions each. “Both losses and gains are bad news for the cell,” says McVean. He and his colleagues predict that such variants are likely to have weak effects on gene activity. But those slight changes in gene activity might make big differences in disease risk, he says.

Because rare variants tend to be new, they are usually restricted in geographic or ethnic distribution. For that reason, doctors someday will have to consider individuals’ heritage when trying to figure out which of many genetic variants contribute to a particular disease.

If genetic analysis is ever going to be clinically useful, researchers will have to gauge the genetic diversity of millions of people, McVean says. Although the project has cataloged its eponymous number of genomes, he says, it will officially wrap up only after the researchers have deciphered the genetic makeup of 2,500 people.